Although oligosaccharide synthesis has developed in leaps and bounds in the last decade or so, this goal is still a long way off. The reasons for this are multiple and reside in the complexity of the chemistry of formation of glycosidic bonds. An absolutely overwhelming number of methods toward this end have been devised, however, the vast majority of these have been developed empirically and they are therefore underpinned by very little detailed understanding of mechanism. The thesis of this proposal is that the rationalization and improvement of oligosaccharide is best be brought about by a two pronged approach. One prong is the detailed investigation of the mechanisms of a few of glycosylation reactions with the aim of providing a sound basis for further development. The second prong, which can not be entirely separated from the first, is the careful development of improved methodology, with a focus on the more challenging problems. In the mechanistic prong we will investigate the underlying basis for possible neighboring group participation by esters at positions other than the familiar 2-position. The emphasis will be on the detection of bridging intermediates by chemical and spectroscopic methods. In the synthetic prong we will build on our extensive preliminary results to develop a method for the stereoselective synthesis of sialic acid glycosides, with an emphasis on the 1-glycosides of N-glycolyl neuraminic acid and KDO. We will also develop methods for the synthesis of glycopeptides linked based on the labile glycosyl ester motif. PUBLIC HEALTH RELEVANCE: The goal of modern oligosaccharide synthesis is the efficient production of natural and unnatural oligosaccharides, and their mimetics, capable of interfering constructively in disease states. This interference may be brought about by the blocking of oligosaccharide processing enzymes, by disruption of bacterial cell wall biosynthesis, by modulating cell-cell recognition, by enhancing binding and selectivity of drugs to DNA, and by the provision of antigenic oligosaccharides in synthetic vaccines. All of these very desirable processes require the highly efficient synthesis of oligosaccharides. The goal of this project is to provide methods for the synthesis of the more challenging classes of glycosidic bond and to display these methods through the synthesis of biologically relevant oligosaccharides and glycopeptides.